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Bibliometric analysis has recently become a popular and rigorous technique used for exploring and analyzing the literature in business and management. Prior studies principally focused on 'how to do bibliometric analysis', presenting an overview of the bibliometric methodology along with various techniques and step-by-step guidelines that can be relied on to rigorously conduct bibliometric analysis. However, the current body of evidence is limited in its ability to provide practical knowledge that can enhance the design and performance of bibliometric research. This claim is supported even by the fact that relevant studies refer to their work as 'bibliometric analysis' rather than 'bibliometric research'. Accordingly, we endeavor to offer a more functional framework for researchers who wish to design/conduct bibliometric research on any field of research, especially business and management. To do this, we followed a twofold way. We first outlined the main stages and steps of typical bibliometric research. Then, we proposed a comprehensive framework for specifying how to design/conduct the research and under what headings the relevant stages (step-by-step) will be used and/or presented. Thus, the current paper is expected to be a useful source to gain insights into the available techniques and guide researchers in designing/conducting bibliometric research. [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine the impact of nano-clay and nano-silica particles on the vibrational characteristics of composite cylindrical panels in corrosive environments. In this context, due to the presence of diluted sulfuric acid as the corrosive solution, the coupling effects of material degradation and hygroscopic loading on the natural frequencies are taken into consideration. In order to achieve this, it is first explored through experiment how adding nanoparticles affects the coefficient of hygroscopic expansion of the glass/epoxy specimens. Using this coefficient, the in-plane loading caused by corrosive solution is then applied in the equations. The mechanical properties and hygroscopic expansion coefficients of the composite samples exposed to the corrosive environment are first determined by certain experimental testing. The equations of motion are derived using the first-order shear deformation theory (FSDT), and the vibration problem is solved using the generalized differential quadrature (GDQ) technique. Investigation is conducted into the effects of various nanoparticles, immersion time, geometrical elements, and boundary conditions on the natural frequencies of the cylindrical panels. It is found that adding nanoparticles can significantly improve the mechanical properties, the corrosion resistance, and the natural frequencies of composites in which the nano-clay is more effective. For example, adding nano-clay and nano-silica particles, respectively, results in 32.32% and 26.29% increase in elasticity modulus of reinforced glass/epoxy composite. In addition, 12.71% and 47.32% improvements are observed in the natural frequency of the nano-clay reinforced composite panel before and after 90 days of immersion in sulfuric acid. In comparison, the nano-silica particles are responsible for 7.80% and 23.03% increase in natural frequency before and after immersion time. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential to maintain immune homeostasis by promoting self-tolerance. Reduced Treg numbers or functionality can lead to a loss of tolerance, increasing the risk of developing autoimmune diseases. An overwhelming variety of human Tregs has been described, based on either specific phenotype, tissue compartment, or pathological condition, yet the bulk of the literature only addresses CD25-positive and CD127-negative cells, coined by naturally occurring Tregs (nTregs), most of which express the transcription factor Forkhead box protein 3 (FOXP3). While the discovery of FOXP3 was seminal to understanding the origin and biology of nTregs, there is evidence in humans that not all T cells expressing FOXP3 are regulatory, and that not all Tregs express FOXP3. Namely, the activation of human T cells induces the transient expression of FOXP3, irrespective of whether they are regulatory or inflammatory effectors, while some induced T cells that may be broadly defined as Tregs (e.g., Tr1 cells) typically lack demethylation and do not express FOXP3. Furthermore, it is unknown whether and how many nTregs exist without FOXP3 expression. Several other candidate regulatory molecules, such as GITR, Lag-3, GARP, GPA33, Helios, and Neuropilin, have been identified but subsequently discarded as Treg-specific markers. Multiparametric analyses have uncovered a plethora of Treg phenotypes, and neither single markers nor combinations thereof can define all and only Tregs. To date, only the functional capacity to inhibit immune responses defines a Treg and distinguishes Tregs from inflammatory T cells (Teffs) in humans. This review revisits current knowledge of the Treg universe with respect to their heterogeneity in phenotype and function. We propose that it is unavoidable to characterize human Tregs by their phenotype in combination with their function, since phenotype alone does not unambiguously define Tregs. There is an unmet need to align the expression of specific markers or combinations thereof with a particular suppressive function to coin functional Treg entities and categorize Treg diversity. [ABSTRACT FROM AUTHOR]

Living with spinal cord injury (SCI) is a challenge that begins in the acute phase, when the disease, the limitations, and the treatments fill the days at the hospital. This study aims to understand the healthcare experience of the person with SCI in the acute phase, based on the Activities of Living Nursing Model (ALNM). It is a qualitative and phenomenological study based on the Standards for Reporting Qualitative Research. Data were collected via semi-structured interviews. Content analysis was performed using the ATLAS.ti software and Bardin's methodology. The article was written following the COREQ guidelines. The categories were defined using the Roper–Logan–Tierney Model for Nursing. The sample included 16 people with incomplete SCI, different etiology, and neurological levels. Eleven of the twelve ALNM emerged from the interviews. The activities of mobilizing, eliminating, maintaining a safe environment, and communicating were emphasized the most. Controlling body temperature was not relevant. Mobility deficits and pain increased dependence. Feelings of motivation, encouragement, and frustration were highlighted. Professional expertise, rehabilitation resources, and support equipment promoted independence. The results in this sample revealed that people with SCI in the acute phase have complex challenges related to dependence awareness and treatments, but they always keep recovery expectations in mind. [ABSTRACT FROM AUTHOR]

Numerical simulations of seismic site response require the characterization of the nonlinear behaviour of shallow subsoil. When extensive evaluations are of concern, as in the case of seismic microzonation studies, funding problems prevent from the systematic use of laboratory tests to provide detailed evaluations. For this purpose, 485 shear modulus reduction, G\G0(γ) and damping ratio, D(γ) curves were collected from multiple literature sources available in Italy. Each curve was associated with the related engineering geological units considered in seismic microzonation studies. A statistical analysis of the data was carried out with the aim of shedding light on the significant difference between the laboratory classification of samples and the macroscopic/engineering geological one, provided during seismic microzonation studies. Since the engineering geological classification plays a prominent role in extensive site response evaluations, the outcomes of the present work may be of help at least when preliminary seismic response estimates are of concern. The dataset provides reference information that can serve as key data for large-scale hazard assessments worldwide. [ABSTRACT FROM AUTHOR]

Background: Several systemic conditions can result in distinct degrees of salivary gland damage and consequent hypofunction. The development of successful management schemes is highly challenging due to the complexity of saliva. This study aimed to systematically map the literature on the physical stimulation of salivary glands for hyposalivation management and the response of individuals according to different systemic conditions causing salivary impairment. Methods: A systematic search in the literature was performed. Two reviewers independently selected clinical trials, randomized or not, that used physical stimulation to treat hyposalivation caused by systemic conditions. Studies evaluating healthy subjects without hyposalivation were included as controls. Single-arm clinical studies or case series were also included for protocol mapping (PRISMA extension for scoping reviews). Results: Out of 24 included studies, 10 evaluated healthy subjects, from which 9 tested transcutaneous electrical nerve stimulation (TENS) and 1 tested acupuncture and electroacupuncture. Fourteen studies evaluated individuals with hyposalivation: 6 applied TENS, 6 applied low-level laser therapy (LLLT), and 2 applied acupuncture, carried out in post-chemotherapy, medication use, postmenopausal women, hemodialysis patients, smokers, diabetics, Sjögren's syndrome (SS). All showed increased salivation after treatment, except for two LLLT studies in individuals with SS. Conclusions: Among the different patient groups, individuals with Sjögren's syndrome (SS) exhibited the poorest responses, while those with medication-induced hyposalivation demonstrated the most favorable treatment outcomes, independently of the management strategy for saliva stimulation. It means that physical stimulation of salivary glands holds promise as an alternative for managing hyposalivation in cases of reversible gland damage. However, to make informed decisions in current practice, it is necessary to conduct new well-designed randomized clinical trials with appropriate methodologies. [ABSTRACT FROM AUTHOR]

Sodium selenite modulates the activity of lymphocytes. It negatively regulates the suppressive activity of cells and increases the immune response. In this study, we evaluated whether the regulatory T cell differentiation was modulated by sodium selenite. The percentages of CD4+CD25+Foxp3+, CD4+CD25+, and CD4+CTLA-4+ cells in CD4+ T cells cultures stimulated with IL-2 and TGF-β in the presence or absence of selenium, in the form of sodium selenite (2.0×10−6M), were evaluated by flow cytometry. The mRNA expression of TET2/3 enzymes and IL-10 was analyzed by RT-qPCR and the levels of IL-10 were measured by an ELISA. We observed a decrease in CD4+CD25+Foxp3+ and CD4+CTLA-4+ cells in presence of selenium. However, normal percentages were reached again after selenium removal. An increase in CD4+CTL4-4+ cells was detected in selenium-primed cell cultures in absence of IL-2 and TGF-β. In addition, we observed a decrease in TET3 in presence of selenium. Finally, we observed an augment in IL-10 transcription and protein levels and relative expression of TET2 in cultures exposed to selenium. We suggest that selenium reversibly affects the regulatory T cell differentiation in vitro. Likewise, selenium may modulate Treg percentages promoting optimal immune responses and, at the same time, the expression of specific suppressor molecules. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and coinhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology. [ABSTRACT FROM AUTHOR]

In this study, we extracted the in‐situ soil dynamic parameters that contains shear wave velocity, shear modulus degradation curve and damping ratio from seismic data recorded at the Delaney Park Digital Array (DPDA) during the 2018 Mw 7.0 Anchorage earthquake. Based on these parameters, a one‐dimensional finite element model in DEEPSOIL is constructed to simulate the propagation of seismic waves in near‐surface, and the simulated pseudo‐spectral accelerations with 5% damping from the in‐situ soil dynamic parameters are compared with those from different velocity profiles and damping models. The results show that: (1) it is necessary to consider the effects of downward waves on the estimation of shear strain when extracting the modulus degradation curve, otherwise the shear strain will be overestimated by several times at this site; (2) the validity and reliability of the use of the in‐situ soil dynamic parameters in reproducing and predicting nonlinear ground response are verified, in which the Pearson correlation coefficients between the simulated and observed spectral accelerations at different depths for five selected events are generally higher than 0.95; (3) the ground response analysis exhibits relatively high sensitivity to both velocity profiles and damping models, where the velocity profile extracted from vertical seismic data obviously outperforms other velocity profiles, and the Rayleigh damping provides an alternative to the constant damping model in this study. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormone metabolism disrupts after cardiopulmonary bypass both in adults and pediatric patients. This is known as Euthyroid sick syndrome, and it is more evident in pediatric patients who were undergoing complex cardiac surgeries compared to adults. This decrease in serum T3 levels increases the incidence of low cardiac output, requirement of inotropes, prolonged mechanical ventilation, and prolonged intensive care unit (ICU) stay. Aims and Objectives: The primary objective was to compare the mean Vasoactive-inotropic score (VIS) at 72 hours postoperatively between T3 and Placebo groups. Materials and Methods: One hundred patients were screened, and 88 patients were included in the study. Triidothyronine 1 mic/kg 10 doses 8th hourly was given orally postoperatively to cases and sugar sachets to controls. The blood samples for analysis of FT3, FT4, and TSH were taken every 24 hours postoperatively, and baseline values were taken after induction. Mean VIS scores, ejection Fraction (EF), Left ventricular outflow tract velocity time integral (LVOT VTi), hemodynamics and partial pressure of oxygen/ fraction of inspired oxygen(PaO2/FiO2) were recorded daily. Results: The Mean VIS scores at 72 Hours postoperatively were significantly less in the T3 group (5.49 ± 6.2) compared to the Placebo group (13.6 ± 11.7). The PaO2/FiO2 ratios were comparatively more in the T3 group than the Placebo group. The serum levels of FT3 FT4 were significantly higher in the T3-supplemented group than the Placebo group. The VIS scores were significantly lower from 48 hours postoperatively in children < 6 months of age. Conclusion: In this study, we observed that supplementing T3 postoperatively decreases the ionotropic requirement from 72 hours postoperatively. This is more useful in children <6 months of age undergoing complex cardiac surgeries. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the leading causes of global cancer-related mortality. Tumor-infiltrating effector immune cells play critical roles in tumor control, and their activity can dictate disease outcomes. In this study, we provide evidence of the associations between different CD8+ T cell subpopulations with disease-free survival (DFS) in CRC patients. We report associations between higher levels of certain circulating and tumor-infiltrating CD8+ T cell subsets and improved clinical outcomes in CRC patients. T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3−Helios−TIM-3+ and FoxP3−Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios−TIM-3+ Tregs were associated with better DFS. [ABSTRACT FROM AUTHOR]

Immune checkpoint receptors are key players in regulating the immune response. They are responsible for both generating an immune response sufficient to kill invading pathogens, balancing the same response, and protecting against tissue destruction or the development of autoimmune events. The central role of the co-inhibitory receptors also referred to as inhibitory immune checkpoints, including PD-1 and CTLA-4 has become especially evident with the cancer treatments targeting these receptors. Blocking these pathways enhances the immune activity, resulting in both an increased chance of cancer clearance, at the same time induction of immune-related adverse events (irAE). Some of these irAE progress into actual autoimmune diseases with autoantibodies and symptoms, undistinguished from the naturally occurring diseases. This review will take advantage of the lessons learned from immune checkpoint blockade and relate this knowledge to our understanding of the same pathways in naturally occurring autoimmune diseases, mainly focusing on rheumatic diseases. [ABSTRACT FROM AUTHOR]

The article presents the discussion on forensic analysis of seismograph recordings from strong motion earthquakes. Topics include using vertical array data available historically for two of the urban sites considered by the authors and some consequences for back-analysis; and kinematic interaction ratio of the buildings to the underlying soil being higher.

Simple Summary: Tumor necrosis factor (TNF) receptor-2 (TNFR2) affects tumor development and metastasis in several ways. TNFR2 promotes tumor immune escape by virtue of its ability to stimulate various immune suppressive cell types, e.g., regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and can act as an oncogene. However, TNFR2 also elicits antitumoral activities by costimulation of cytotoxic T-cells. Accordingly, antagonists and agonists targeting TNFR2 have been preclinically evaluated for tumor therapy and have demonstrated anti-tumor activity in preclinical studies. In this review, we summarize the most important TNFR2-related findings regarding tumor biology and cancer therapy and especially discuss the mode of action of currently used agonists and antagonists of TNFR2. Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists. [ABSTRACT FROM AUTHOR]

The average shear-wave velocity of the first 30 metres of subsoil and the depth of the engineering bedrock are considered the key parameters for simplified seismic site response modelling. However, a reliable estimate of the site amplification should consider the entire shear-wave velocity profile from the ground surface down to the engineering bedrock. In deep alluvial basins, a typical geological context where the soil–bedrock interface may lie below the penetration depth of most common prospecting methods, only the shallow velocity profile can be defined in detail, while the deeper structures are commonly extrapolated with linear equations. The choice of a realistic interpolation between the shallow and deep soil still remains an open issue. We compute the 1D seismic site response of two sectors of the Venetian Plain (Northern Italy) characterised by gravelly and sandy deep formations. We model the 1D soil columns using theoretical non-linear gradients proposed in literature for deep alluvial basins. The numerical modelling results, in terms of strong motion parameters, show variations in the seismic site response up to 20%. The effect of the velocity gradients is also evaluated comparing the numerical simulations with real accelerometers recorded by a deep borehole seismometer and a seismic station located at the top of the borehole. These results demonstrate that the selection of the velocity gradient is crucial for seismic site characterisation of deep alluvial basins. In particular, the study suggests which is the most conservative gradient among the ones tested in terms of ground motion hazard estimation. [ABSTRACT FROM AUTHOR]

Typical seismic ground-motion models predict the response spectral ordinates (GMM-SA), which are the damped responses of a suite of single-degree-of-freedom oscillators. Response spectra represent the response of an idealized structure to input ground-motion, but not the physics of the actual ground-motion. To complement the regionally adaptable GMM-SA of Kotha et al. (2020), we introduce a model capable of predicting Fourier amplitudes (GMM-FA); developed from the Engineering Strong Motion (ESM) dataset for pan-Europe. This GMM-FA reveals the very high variability of high frequency ground-motions, which are completely masked in a GMM-SA. By maintaining the development strategies of GMM-FA identical to that of the GMM-SA, we are able to evaluate the physical meaning of the spatial variability of anelastic attenuation and source characteristics. We find that a fully data-driven geospatial index, Activity Index (AIx), correlates well with the spatial variability of these physical effects. AIx is a fuzzy combination of seismicity and crustal parameters, and can be used to adapt the attenuation and source non-ergodicity of the GMM-FA to regions and tectonic localities sparsely sampled in ESM. While AIx, and a few other parameters we touch upon, may help understand the spatial variability of high frequency attenuation and source effects, the high frequency site-response variability—dominating the overall aleatory variance—is yet unresolvable. With the rapid increase in quantity and quality of ground-motion datasets, our work demonstrates the need to upgrade regionalization techniques, site-characterisation, and a paradigm shift towards Fourier ground-motion models to complement the traditional response spectra prediction models. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells are critical for the maintenance of immune homeostasis. Dysregulation of Treg cells has been implicated in the pathogenesis of autoimmunity and chronic inflammation, while aging is characterized by an accumulation of inflammatory markers in the peripheral blood, a phenomenon known as 'inflammaging'. The relationship between Treg cells and age‐related diseases remains to be further studied. Increasing evidence revealed that Treg cells' dysfunction occurs in aged patients, suggesting that immune therapies targeting Treg cells may be a promising approach to treat diseases such as cancers and autoimmune diseases. Furthermore, drugs targeting Treg cells show encouraging results and contribute to CD8+ T‐cell‐mediated cytotoxic killing of tumor and infected cells. In general, a better understanding of Treg cell function may help us to develop new immune therapies against aging. In this review, we discuss potential therapeutic strategies to modify immune responses of relevance for aging to prevent and treat age‐related diseases, as well as the challenges posed by the translation of novel immune therapies into clinical practice. [ABSTRACT FROM AUTHOR]

Sleep hygiene is well-established in the scope of occupational therapy practice; however, this occupation is rarely addressed in the intensive care unit (ICU). The majority of health care practitioners believe patients experience reduced sleep quality in the ICU, which can negatively impact patient outcomes. Through a review of the literature, this paper identifies common factors that negatively influence sleep quality and duration and proposes evidence-based interventions to improve patients’ sleep. Factors that influence sleep and fall in the domain of occupational therapy practice include the environment, psychosocial elements, and patient care. Occupational therapists can use interventions, such as orienting patients during the day, creating sleep-promoting routines, and educating patients on the use of adaptive equipment (earplugs, eye masks, or sound machines for relaxing music). Role confusion and a lack of prioritization of sleep have led to the occupation of rest and sleep not being addressed. This paper will suggest implications for the future of the profession that includes establishing leadership positions on a multidisciplinary team to improve patients’ sleep. [ABSTRACT FROM AUTHOR]

Copyright of Journal of the Society of Thoracic Carido-Vascular Anaesthesia & Intensive Care is the property of Gogus Kalp Damar Anestezi ve Yogun Bakim Dernegi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective - Corporate concern for the environment is an important stakeholder demand. A company is obliged to preserve the environment with various investments, one of which is green intellectual capital to maintain the sustainability of the company, especially for companies that carry out their business activities in countries that are in conditions of high pollution such as Indonesia. The importance of green intellectual capital investment information for stakeholders can be seen from the value relevance of the information. This study aims to examine and analyze the effect of investment in green intellectual capital, which consists of the following dimensions: human, structural, and relation to value relevance. Methodology/Technique -- This study will explain the causal relationship between the independent and the dependent variables through hypothesis testing based on the theory that has been formulated with data that obtained and tested through quantitative panel data testing. Findings - The results of a survey of 515 samples of data from a population of 183 manufacturing companies listed on the Indonesia Stock Exchange (IDX) in 2015-2019 found that green intellectual capital with its three dimensions had a significant positive effect on value relevance. This study also proves that green structural intellectual capital has influenced more on value relevance than human and relation intellectual capital. Novelty - The measurement of variables is green intellectual capital and value relevance in this study develops previous research with related government conditions and regulations in Indonesia. Green intellectual capital investment is measured by using content analysis from disclosures in annual reports and sustainability reports, and value relevance is measured by the Olhson model with beta correction by the stock market in Indonesia. [ABSTRACT FROM AUTHOR]

Reversion of immune sensitization tests for Mycobacterium tuberculosis (M.tb) infection, such as interferon-gamma release assays or tuberculin skin test, has been reported in multiple studies. We hypothesized that QuantiFERON-TB Gold (QFT) reversion is associated with a decline of M.tb-specific functional T cell responses, and a distinct pattern of T cell and innate responses compared to persistent QFT+ and QFT- individuals. We compared groups of healthy adolescents (n=~30 each), defined by four, 6-monthly QFT tests: reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent positives (QFT+/+/+/+). We stimulated peripheral blood mononuclear cells with M.tb antigens (M.tb lysate; CFP-10/ESAT-6 and EspC/EspF/Rv2348 peptide pools) and measured M.tb-specific adaptive T cell memory, activation, and functional profiles; as well as functional innate (monocytes, natural killer cells), donor-unrestricted T cells (DURT: γδ T cells, mucosal-associated invariant T and natural killer T-like cells) and B cells by flow cytometry. Projection to latent space discriminant analysis was applied to determine features that best distinguished between QFT reverters, non-converters and persistent positives. No longitudinal changes in immune responses to M.tb were observed upon QFT reversion. M.tb-specific Th1 responses detected in reverters were of intermediate magnitude, higher than responses in QFT non-converters and lower than responses in persistent positives. About one third of reverters had a robust response to CFP-10/ESAT-6. Among those with measurable responses, lower proportions of TSCM (CD45RA+CCR7+CD27+) and early differentiated (CD45RA-) IFN-γ-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed in reverters compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in reverters compared to persistent-positives. No differences in M.tb-specific innate, DURT or B cell functional responses were observed between the groups. Statistical modelling misclassified the majority of reverters as non-converters more frequently than they were correctly classified as reverters or misclassified as persistent positives. These findings suggest that QFT reversion occurs in a heterogeneous group of individuals with low M.tb-specific T cell responses. In some individuals QFT reversion may result from assay variability, while in others the magnitude and differentiation status of M.tb-specific Th1 cells are consistent with well-controlled M.tb infection. [ABSTRACT FROM AUTHOR]

The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage. [ABSTRACT FROM AUTHOR]

Idiopathic CD4 T cell lymphocytopenia (ICL) is a rare entity characterized by CD4 T cell count of <300 cells/mm3 along with opportunistic infection for which T cell marker expression remains to be fully explored. We report an ICL case for which T lymphocyte phenotype and its costimulatory molecules expression was analyzed both ex vivo and after overnight stimulation through CD3/CD28. The ICL patient was compared to five healthy controls. We observed higher expression of inhibitory molecules PD-1/PDL-1 and CTLA-4 on CD4 T cells and increased regulatory T cells in ICL, along with high activation and low proliferation of CD4 T cells. The alteration in the expression of both the costimulatory pathway and the apoptotic pathway might participate to down-regulate both CD4 T cell functions and numbers observed in ICL. [ABSTRACT FROM AUTHOR]

To complement the new European Strong-Motion dataset and the ongoing efforts to update the seismic hazard and risk assessment of Europe and Mediterranean regions, we propose a new regionally adaptable ground-motion model (GMM). We present here the GMM capable of predicting the 5% damped RotD50 of PGA, PGV, and S A T = 0.01 - 8 s from shallow crustal earthquakes of 3 ≤ M W ≤ 7.4 occurring 0 < R JB ≤ 545 km away from sites with 90 ≤ V s 30 ≤ 3000 m s - 1 or 0.001 ≤ s l o p e ≤ 1 m m - 1 . The extended applicability derived from thousands of new recordings, however, comes with an apparent increase in the aleatory variability (σ). Firstly, anticipating contaminations and peculiarities in the dataset, we employed robust mixed-effect regressions to down weigh only, and not eliminate entirely, the influence of outliers on the GMM median and σ. Secondly, we regionalised the attenuating path and localised the earthquake sources using the most recent models, to quantify region-specific anelastic attenuation and locality-specific earthquake characteristics as random-effects, respectively. Thirdly, using the mixed-effect variance–covariance structure, the GMM can be adapted to new regions, localities, and sites with specific datasets. Consequently, the σ is curtailed to a 7% increase at T < 0.3 s, and a substantial 15% decrease at T ≥ 0.3 s, compared to the RESORCE based partially non-ergodic GMM. We provide the 46 attenuating region-, 56 earthquake localities-, and 1829 site-specific adjustments, demonstrate their usage, and present their robustness through a 10-fold cross-validation exercise. [ABSTRACT FROM AUTHOR]

Starting with the destructive 1985 Michoacan Mw 8·0 earthquake, the lake zone of Mexico City has been experiencing ground motions bearing the effects of strong soil amplification at specific site-dependent periods. Last year's Mw = 7·1 Puebla earthquake, although less damaging, with different orientation and mechanism, and at a much shorter distance than the 1985 event, nevertheless produced records bearing similar soil amplification effects and even rather similar motions on rock. This paper concentrates on four sites, distinguished mainly by the thickness of the soft clay, on which three to seven seismic events (with Mw > 6·5) have been recorded. Using the corresponding records on two hilly zone sites as base rock motions, amplification functions in terms of ratios of top-over-base recorded acceleration response spectra are studied. Although the dominant periods of each amplification function confirm the occurrence of resonance at the fundamental natural period of each particular soil stratum, differences between the amplification functions of the east–west and north–south components are evident. Using the actual soil profile of two of these stations, along with the G:γ and ξ:γ curves from the general literature and from site-specific measurements, one-dimensional wave propagation analyses are conducted. Reasonable agreement with the records is generally found in terms of response spectra. However, weak motions recorded in some events (where soil behaved essentially linearly) exhibit a number of beating cycles which last for almost one additional minute beyond 60 s, and which are barely noticeable in the computed motions. An oversimplified (in geometry and properties) two-dimensional basin, 6 km long, containing 60 m of Mexico City clay, is analysed with finite elements, excited by the rock outcrop hilly zone records. Wave propagation in this basin reveals the generation of Rayleigh waves at the edge, which move towards the centre and interfere with the incident and reflected S and P waves. The resulting motions away from the edge resemble the recorded motions at the CAO site in a 1999 earthquake better than the one-dimensional analysis, but are still far from satisfactorily reproducing the beating. An additional factor to qualitatively explain reality is generically examined: the oscillations of a tall (15-storey) building and the feedback of its free oscillations into the ground (soil–building–soil interaction) are found to increase free-field accelerations slightly. [ABSTRACT FROM AUTHOR]

Based on the third-order shear deformation theory (TSDT), this paper numerically investigates the natural frequencies and time response of three-layered annular plate with functionally graded materials (FGMs) sheet core and piezoelectric face sheets, under initial external electric voltage. The impressive material specifications of FGM core are assumed to vary continuously across the plate thickness utilizing a power law distribution. The equilibrium equations are obtained employing Hamilton's method and then solved applying differential quadrature method (DQM) in conjunction with Newmark-ß. Numerical studies are carried out to express the influences of the external electric voltage, aspect ratio, and material gradient on the variations of the natural frequencies and time response curves of FGM piezoelectric sandwich annular plate. It is precisely shown that these parameters have considerable effects on the free vibration and transient response. [ABSTRACT FROM AUTHOR]

This paper presents the development of a probabilistic seismic hazard analysis (PSHA) model to compute seismic hazard maps for the French territory taking into account 15 years of research and development in the area. Since 2002, when the first probabilistic hazard map was computed for France, many new data became available leading to new studies and experience gained. This 2017 PSHA version for France incorporates significant improvements over previous version. In particular, the recent SIGMA project 2010–2016 produced a number of outputs which are used in the present analysis: a homogenized earthquake catalogue in moment magnitude (Mw), a Bayesian methodology to compute distributions of maximum magnitudes, ground motion prediction equations specifically developed for the French territory, new seismotectonic analysis conducted based on geological, structural, geophysical, neotectonic and seismological data. Preliminary comparison of median PGA values at 475 years return period with results obtained independently for neighboring countries (Germany, Switzerland, and Italy) reveals a fair agreement. Comparison with the 2013 European Seismic Hazard Model (ESHM13, SHARE project) and the model for France developed in 2002 indicates that 2017 PSHA version leads to lower hazard. [ABSTRACT FROM AUTHOR]

Large-scale simulations and forensic analyses of the seismic behaviour of real case studies are often based on simplified analytical approaches to estimate the reduction in fundamental frequency and the amount of radiation damping induced by dynamic soil-foundation-structure (SFS) interaction. The accuracy of existing closed-form solutions may be limited because they were derived through single degree-of-freedom structural models with shallow rigid foundations placed on a homogeneous, linear elastic half-space. This paper investigates the effectiveness of those formulations in capturing the dynamic out-of-plane response of single load-bearing walls within unreinforced masonry buildings having either a shallow foundation or an underground storey embedded in layered soil. To that aim, analytical predictions based on the replacement oscillator approach are compared to results of two-dimensional dynamic analyses of coupled SFS elastic models under varying geotechnical and structural properties such as the soil stratigraphy, foundation depth and number of building storeys. Regression models and a relative soil-structure stiffness parameter are proposed to quickly predict the frequency reduction induced by SFS interaction, accounting for the presence of an embedded foundation, an underground storey and a layered soil. The effects of SFS interaction are also evaluated in terms of equivalent damping ratio, showing the limitations of simplified approaches. Since the geometric layouts considered in this study are rather recurrent in the Italian and European built heritage, the proposed procedure can be extended to similar structural configurations. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) treatment monitoring is paramount to clinical decision-making and the host biomarkers appears to play a significant role. The currently available diagnostic technology for TB detection is inadequate. Although GeneXpert detects total DNA present in the sample regardless live or dead bacilli present in clinical samples, all the commercial tests available thus far have low sensitivity. Humoral responses against Mycobacterium tuberculosis (Mtb) antigens are generally low, which precludes the use of serological tests for TB diagnosis, prognosis, and treatment monitoring. Mtb-specific CD4+ T cells correlate with Mtb antigen/bacilli burden and hence might serve as good biomarkers for monitoring treatment progress. Omics-based techniques are capable of providing a more holistic picture for disease mechanisms and are more accurate in predicting TB disease outcomes. The current review aims to discuss some of the recent advances on TB biomarkers, particularly host biomarkers that have the potential to diagnose and differentiate active TB and LTBI as well as their use in disease prognosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation. [ABSTRACT FROM AUTHOR]

Purpose: The role of cytokine-producing B cells in antitumor immunity is mostly overlooked. In the present study, we investigated changes in B cell cytokine profiles in breast tumor-draining lymph nodes (TDLNs) during disease progression, and associations of these changes with prognostic indicators. Methods: Flow cytometry was used to measure the expression of TNF-α, IL-10, TGF-β, IL-2 and IFN-γ in B cells from 42 axillary lymph nodes. The frequencies of IL-10+ and FoxP3+ T regulatory cells (Tregs) were also determined. Results: No significant changes in B cell cytokine profiles were observed during breast cancer progression from stage I to III, but the percentage of B cells with high TNF-α expression (TNFhi) showed a negative relationship with lymph node involvement and Her2 expression (p < 0.05). The percentage of IL-10+ B cells was found to be significantly higher in non-metastatic lymph nodes in node-negative compared to node-positive patients (p = 0.001). The frequencies of IL-10+ and TNFhi B cells were found to be negatively correlated with the number of involved lymph nodes. The frequency of TNFhi B cells showed an inverse correlation with the frequency of FoxP3+ Tregs, which in turn was associated with indicators of a poor prognosis. Conclusions: Our data indicate that the cytokine profiles of B cells in TDLNs of patients with breast cancer show associations with various disease parameters. TNFhi and IL-10+ B cells correlated positively with indicators of a good prognosis. Further functional studies are required to elucidate the role of cytokine production by B cells in immunity against breast cancer. [ABSTRACT FROM AUTHOR]

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Introduction: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children. Methods: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score–matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors. Results: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children. Conclusion: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation. [ABSTRACT FROM AUTHOR]

We introduce in the on-site earthquake early warning (EEW) a partially non-ergodic perspective from the site effects point of view. We consider the on-site EEW approach where the peak ground velocity (PGV) for S waves is predicted from an early estimate, over the P waves, of either the peak-displacement (PD) or cumulative squared velocity (IV2). The empirical PD-PGV and IV2-PGV relationships are developed by applying a mixed-effect regression where the site-specific modifications of ground shaking are treated as random effects. We considered a large data set composed of almost 31 000 selected recordings in central Italy, a region struck by four earthquakes with magnitude between 6 and 6.5 since the 2009 L'Aquila earthquake. We split the data set into three subsets used for calibrating and validating the on-site EEW models, and for exemplifying their application to stations installed after the calibration phase. We show that the partially non-ergodic models improve the accuracy of the PGV predictions with respect to ergodic models derived for other regions of the world. Moreover, considering PD and accounting for site effects, we reduce the (apparent) aleatory variability of the logarithm of PGV from 0.31 to 0.36, typical values for ergodic on-site EEW models, to about 0.25. Interestingly, a lower variability of 0.15 is obtained by considering IV2 as proxy, which suggests further consideration of this parameter for the design of on-site EEW systems. Since being site-specific is an inherent characteristic of on-site EEW applications, the improved accuracy and precision of the PGV predicted for a target protection translate in a better customization of the alert protocols for automatic actions. [ABSTRACT FROM AUTHOR]

The effectiveness of sleep intervention developed by occupational therapists was reviewed, and a conceptual framework for organizing the developing practice of sleep management in occupational therapy was proposed in this paper. Evidence-based articles on sleep management practice in occupational therapy from 2007 to 2017 were retrieved. Four types of effective sleep management intervention were identified from the literature, including the use of assistive devices/equipment, activities, cognitive behavioral therapy for insomnia, and lifestyle intervention, and the use of assistive device was the most popular intervention. Applying the Person-Environment-Occupation Performance (PEOP) framework, we developed a conceptual framework for organizing occupational therapy practice in sleep management. The future development of occupation-based sleep intervention could focus on strategies to (1) minimize the influence of bodily function on sleep, (2) promote environment conducive to sleep, and (3) restructure daytime activity with a focus on occupational balance. [ABSTRACT FROM AUTHOR]

There is now compelling evidence that TNF receptor type II (TNFR2) is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation. [ABSTRACT FROM AUTHOR]

Treatment with activated autologous lymphocytes (AALs) has demonstrated mixed results for cancer treatment. Preliminary results revealed that the proportion of cluster of differentiation (CD)8+CD57+ T cells is significantly increased in AALs, indicating that they are able to determine treatment outcome. Therefore, the role of CD8+CD57+ T cells in AAL efficacy was investigated. T lymphocytes were isolated from 35 patients with stage IV gastric carcinomas (17 men and 18 women; aged 41‑84 years) receiving immunotherapy using AALs (IAAL). Using fluorescence activated cell sorting, CD8, CD27, CD57, and forkhead box protein 3 (FOXP3) expression was investigated on CD8+ T cell populations in CD8+ T cell differentiation prior to and following in vitro culture. The association between these populations and progression‑free survival (PFS) was analyzed using Cox univariate, and multivariate analyses and Kaplan‑Meier survival analysis. CD57 expression was negative in early‑differentiated CD8+ T cells (CD27+CD8+CD57-), and positive in intermediate‑ (CD27+CD8+CD57+) and terminal‑ (CD27-CD8+CD57+) differentiated CD8+ T cells. Univariate analysis revealed a significant association between terminal‑CD8+ T cells and longer PFS times (P=0.035), whereas CD57-FOXP3+CD8+ T cells were associated with shorter PFS times. Multivariate analysis revealed that CD57-FOXP3+CD8+ T cells was an independent poor prognostic factor, whereas CD57+FOXP3+CD8+ T cells were not associated with PFS. Although IAAL increased the proportion of terminal‑CD8+ T cells relative to the pre‑culture proportions, patients with a high CD57-FOXP3+CD8+ T cell percentage exhibited repressed terminal‑CD8+ T cell induction, leading to poor patient prognosis. Terminally differentiated CD27-CD8+CD57+ T cells were responsible for the effectiveness of AALs; however, CD57-FOXP3+CD8+ T cells abrogated their efficacy, possibly by inhibiting their induction. [ABSTRACT FROM AUTHOR]

Various subgroups of CD8+ T lymphocytes do not only demonstrate cytotoxic effects, but also serve important regulatory roles in the body's immune response. In particular, CD8+ regulatory T cells (CD8+ Tregs), which possess important immunosuppressive functions, are able to effectively block the overreacting immune response and maintain the body's immune homeostasis. In recent years, studies have identified a small set of special CD8+ Tregs that can recognize major histocompatibility complex class Ib molecules, more specifically Qa‑1 in mice and HLA‑E in humans, and target the self‑reactive CD4+ T ce​lls. These findings have generated broad implications in the scientific community and attracted general interest to CD8+ Tregs. The present study reviews the recent research progress on CD8+ Tregs, including their origin, functional classification, molecular markers and underlying mechanisms of action. [ABSTRACT FROM AUTHOR]

The accurate evaluation and appropriate treatment of uncertainties is of primary importance in modern probabilistic seismic hazard assessment (PSHA). One of the objectives of the SIGMA project was to establish a framework to improve knowledge and data on two target regions characterized by low-to-moderate seismic activity. In this paper, for South-Eastern France, we present the final PSHA performed within the SIGMA project. A new earthquake catalogue for France covering instrumental and historical periods was used for the calculation of the magnitude-frequency distributions. The hazard model incorporates area sources, smoothed seismicity and a 3D faults model. A set of recently developed ground motion prediction equations (GMPEs) from global and regional data, evaluated as adequately representing the ground motion characteristics in the region, was used to calculate the hazard. The magnitude-frequency distributions, maximum magnitude, faults slip rate and style-of-faulting are considered as additional source of epistemic uncertainties. The hazard results for generic rock condition (Vs30 = 800 m/s) are displayed for 20 sites in terms of uniform hazard spectra at two return periods (475 years and 10,000 years). The contributions of the epistemic uncertainties in the ground motion characterizations and in the seismic source characterization to the total hazard uncertainties are analyzed. Finally, we compare the results with existing models developed at national scale in the framework of the first generation of models supporting the Eurocode 8 enforcement, (MEDD 2002 and AFPS06) and at the European scale (within the SHARE project), highlighting significant discrepancies at short return periods. [ABSTRACT FROM AUTHOR]

Paper describes the extensive work done in the SIGMA project, aimed at improving knowledge on data, methods and tools to better quantify uncertainties in seismic hazard assessment (SHA). The authors cooperated in the study of potential faults and geological structures, earthquake catalogues, selection of ground motion prediction equations, and methods for site effect evaluation suitable for SHA. All the contributions merged into a probabilistic seismic hazard study conducted for three representative sites of the Po Plain in Northern Italy. Po Plain is a low-to-moderate seismicity region, characterized by some critical features, such as blind faulting and deep alluvium sediments, and by scarcity of strong motion data; these sources of uncertainties in seismic hazard estimation are common to other low seismicity areas around the world. Within SIGMA, special care was devoted to: (a) the use of the single station sigma approach inside the probabilistic SHA, (b) the comparative use of generalized attenuation functions to evaluate the hazard contribution of composite fault systems, and (c) the study of the epistemic uncertainties at play when different modelling approaches to site effects are used. [ABSTRACT FROM AUTHOR]

We present a comprehensive scrutiny of the components of the total uncertainty (sigma, σ) of our recent global predictive model (Cauzzi et al. in Bull Earthq Eng 13:1587-1612, 2015. 10.1007/s10518-014-9685-y), with emphasis on their possible dependence on basic model predictors and source region. Our dataset does not allow us to clearly support or reject the adoption of a magnitude-dependent ϕ or τ description, although there is evidence to suggest that τ of large-magnitude events is lower than that of moderate- and small-magnitude events for vibration periods T < ~ 3 s. The distance dependence of ϕ and ϕss in our data is unclear, but near-source residuals exhibit comparatively larger variability, especially at intermediate and long periods, most likely due to the absence of near-source terms (e.g., hanging-wall, directivity) in our predictive model. The variability of the δWes residuals segregated by ground type is magnified at the dominant amplification periods of the site response, and the residuals on EC8 ground-type A are associated with the lowermost spread. The regional dependence of the δWes residuals in our dataset is small up to intermediate periods, and the offset of regional sub-populations with respect to the overall mean of the residuals is practically null. ϕS2S and ϕSS computed based on stations with at least four records are in good agreement with previously published global and regional models, confirming the limited dependence of ϕSS on region and ground type. Compared to other studies, our τ model is enlarged by Pan-European event terms associated to reverse faults, especially those of the 2012 Emilia (Northern Italy) sequence. We propose an alternative τ model that neglects the large spread associated to these event terms. The contribution to τ of poorly recorded events (with less than three records) is effectively minimised by the weighting scheme of Joyner and Boore (Bull Seismol Soc Am 83:469-487, 1993; Bull Seismol Soc Am 84:955-956, 1994) that we used to develop our model. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). In addition, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in upregulation or downregulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases. [ABSTRACT FROM AUTHOR]

There is now compelling evidence that tumor necrosis factor (TNF)-TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2- targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity. [ABSTRACT FROM AUTHOR]